The Primary Goal of Project 3 is to establish more effective treatment of anemia in critically ill infants,[unreadable] who receive multiple red blood cell (RBC) transfusions and who, as a result, face increased risk of[unreadable] infections and other complications. We propose to reduce the number of transfusions by optimizing the[unreadable] use of erythropoietin (r-HuEPO). The extent to which this can be accomplished will be determined using[unreadable] pharmacokinetic (PK) and pharmacodynamic (PD) data from anemic, neonatal infants undergoing RBC[unreadable] transfusions supplemented with data from PK/PD experiments in neonatal sheep. Our overall[unreadable] hypothesis is that treatment of neonatal anemia can be improved by optimizing administration of r-[unreadable] HuEPO through a comprehensive knowledge of the physiology of erythropoiesis and EPO's complex[unreadable] PK/PD behavior. Aim 1 is to identify the PK/PD and physiologic factors important in predicting and[unreadable] maximizing r-HuEPO's erythropoietic effect based on PK/PD studies of anemic infants and neonatal sheep. Aim 2 is to make Bayesian population PK/PD efficacy predictions of r-HuEPO in anemic infants[unreadable] by applying allometric and physiologic scaling and a physiologic-mechanistic PK/PD model developed[unreadable] from the data generated in Aim 1. Aim 3 is to predict the extent to which r-HuEPO's effect (i.e.[unreadable] reduction/elimination of RBC transfusions) can be maximized through an optimal dosing design based[unreadable] on Bayesian Markov Chain Monte Carlo simulations of human clinical trials using the PK/PD model[unreadable] developed in Aim 2. Aim 4 is to validate a safe, non-radioactive r-HuEPO tracer (BioEPO) for use in[unreadable] mechanistic PK/PD studies in sheep and humans. Important physiologic and pharmacologic issues[unreadable] related to neonatal anemia that cannot be elucidated by current methods can be resolved if a safe and[unreadable] effective BioEPO tracer is developed. Project 3 will test 4 hypotheses: 1) Endogenous EPO production[unreadable] rate and plasma level vs. time profiles relate in a predictable manner to changes in hemoglobin vs. time[unreadable] profiles; 2) EPO receptor (EPOR) pool size changes in a predictable way with changes in the degree of[unreadable] anemia and with the degree of exposure to r-HuEPO and EPO; 3) Stress erythropoiesis results in a[unreadable] reduction in the reticulocyte mean residence time in peripheral blood due to reticulocytes being[unreadable] released from the bone marrow in a more mature form; 4) Using an optimized r-HuEPO dosing regimen[unreadable] it is possible to significantly reduce the number of RBC transfusions in lamb experiments designed to[unreadable] mimic transfusion practices in neonatal anemia. We intend to achieve our Primary Goal by a[unreadable] mechanism and model-based approach assisted by powerful tracer methodologies, and through the[unreadable] use of advanced, modern drug development tools such as Bayesian analysis and clinical trial[unreadable] simulations. Our PK/PD analysis will extend the latest developments in receptor-mediated PK/PD[unreadable] analysis and will consider processes taking place on the cellular and receptor level, including anemia-dependent[unreadable] changes that affect the life-span of reticulocytes and RBCs during stress erythropoiesis. We[unreadable] will make use of advanced 125-l-r-HuEPO tracer kinetic methodologies to address Aim 1 and enable[unreadable] elucidation of the factors that impact the efficacy and utility of r-HuEPO for achieving the Primary Goal.[unreadable] Project 3 will interact synergistically with Project 1 and the Core Facility in several key areas of mutual[unreadable] interest, e.g. investigation of RBC volume and RBC life-span and mathematical modeling of the survival[unreadable] of biotinylated RBCs. The Primary Goal in this project and the collaborative work Dr. Veng-Pedersen[unreadable] will provide on Project 1 follow the current trend in clinical practice to reduce the number of neonatal[unreadable] transfusions and support our PPG's theme of optimizing the transfusion management of anemic[unreadable] newborn infants.